PROJECT SUMMARY/ABSTRACT In spite of significant clinical advancement, breast cancer (BC) continues to be a leading cause of global cancer mortality. In almost all cases, this is attributable not to progression of the primary tumor, but rather to the development of secondary malignancies in distant organs, a process termed metastasis. Indeed, one-third of BC patients will develop metastatic disease, and over 90 percent of BC-related deaths are attributable to metastasis. Confounding the development of treatments for metastasis is the ability of disseminated tumor cells (DTCs) to acquire a dormant phenotype within metastatic niches. To date, few specific regulators of dormancy have been identified, and no targeted therapies exist to treat metastasis. Moreover, dormant DTCs may be resistant to systemic chemotherapies, which are the current standards of care for metastatic BC, because these cells persist in a quiescent state. The proposed study will rigorously interrogate the function of SLX4IP, a novel regulator of metastatic dormancy, at the intersection of multiple pathways implicated in tumor progression, including telomere length homeostasis and the transduction of growth-promoting signals in the metastatic niche. To accomplish this goal, this study will incorporate a diverse array of biochemical, molecular, genetic, and pharmacologic techniques, including, but not limited to: protein-protein interaction mapping; quantitative fluorescence microscopy; and CRISPR/Cas9 genome editing in in vitro and in vivo models of BC dormancy. Additionally, this study will assess the clinical utility of SLX4IP as a prognostic biomarker for metastatic BC. These experiments will provide crucial insights into the mechanisms underlying BC dormancy, thereby establishing a foundation for the development and clinical implementation of therapies that improve survival and long-term outcomes for BC patients.